In general, dialdehyde monoacetals have formyl groups which can be easily converted into an amino group, a hydroxyl group, a carboxyl group or an aminocarboxyl group; on the other hand, their acetal group is extremely stable in neutral or basic conditions but can be easily converted into formyl group under acidic conditions. Consequently, using such characteristics, the two terminal groups of the dialdehyde can be easily converted into two different groups and each kind of these compounds is very important since they are very useful as intermediates for synthesis particularly for synthesis of medical, pharmaceutical and agricultural compounds.
Among them, GADMA which is a typical compound of the above-mentioned dialdehyde monoacetal is particularly considered as important.
Heretofore, several methods have been proposed in the prior art as industrial methods of preparing a dialdehyde monoacetal. However, it is preferred that starting materials can be economically and readily obtained as industrial chemical products which are commercially supplied. Accordingly, it has been thought to be advantageous to directly prepare a dialdehyde monoacetal via the reaction of a dialdehyde with a diol.
An example of this direct method is shown by the following reaction formula in which GA which is used as a dialdehyde and EG used as a diol are used to produce GADMA. ##STR1##
According to this reaction scheme, it seems that GADMA is readily produced. However, practically, it is difficult to obtain GADMA in high yield. The reason is that the above-mentioned reaction is an equilibrium reaction and, moreover, there is a chemical equilibrium system between GADMA and the following GADBA which are by-products, at the same time. ##STR2##
Consequently, as far as the above-mentioned reaction method is used, there will be some trouble regarding the isolation of GADMA via distillation of a reaction mixture containing the five following components GA, GADMA, GADBA, EG and water. Moreover, during distillation, low-boiling point compounds such as water are usually removed from the system and consequently, there is an increase of GADBA. For this reason, the yield of the target GADMA is of only 20% maximum with respect to the GA which is a starting material. This is thus a problem. These facts will be further explained on the basis of Comparative Example I-1 described later on.
In a reaction process using the reaction between GA and EG and a catalyst, regarding the synthesis reaction of GADBA via a distillation process, even if the acid catalyst can be removed via separation (in the case where a solid catalyst has been used) or via neutralization (in the case where a catalyst forming a homogenous system has been used), the synthesis reaction of GADBA cannot be completely avoided. This matter will be made clear on the basis of Comparative Example I-1.
JP-B-76004211 proposes as a method for avoiding the synthesis reaction of GADBA during distillation process, to add dropwise a small amount of EG in an excess of GA and in the same time to remove the synthesized water from the reaction system. However, according to this method, the speed of the synthesis of GADBA is higher than the speed of the synthesis of GADMA which is a desired product and thus, this method requires a very precise control under extremely restricted conditions to control the synthesis of GADBA at a suitable speed while removing water. This method is thus very difficult to use industrially.
Further, a method for the industrial preparation of GADMA via a reaction between 2-alkoxy-3, 4-dihydro-2H-pyran and a diol has also been disclosed. This method is also used as an industrial method for the preparation of GADMA (JP-A-49035383). However, the inventors of the present invention have carried out further investigations and experiments to synthesize GADMA on the basis of the method described in the above-mentioned patent publication and have understood that the yield per mole of the GADMA which can be obtained by this method cannot be more than 13% or so (confer comparative Example III-1 of specification of the present invention) with respect of the moles of the starting materiel 2-alkoxy-3, 4-dihydro-2H-pyran. They have also understood that this yield is not industrially sufficient at all.
Moreover, it is explained in the Examples of the former JP-A-49035383 that the yield of the by-produced GADBA is 26% and that GADBA can be easily converted into GADMA by reacting with water. However, according to the investigations of the inventors of the present invention, the reaction between GADBA and water effectively produces GADMA and diol but when trying to isolate by distillation GADMA from the reaction mixture, water is distilled out of the system and consequently the GADMA synthesized are converted into GADBA via the reverse reaction with diol. For this reason, isolation of GADMA as an industrial product is clearly impossible. This matter is clearly proved in Comparative Example II-1 of the present description.
Thus, it has to be noticed that the synthesis method of GADMA from by-product GADBA as proposed in the previous document JP-A-49035383 is difficult to be used in practice.
The first problem of the present invention is to find out a method of producing dialdehyde monoacetals in high yield which are useful as intermediate products for producing medicines, agricultural chemicals or the like, using dialdehydes and diols as starting materials.
The second and third problems of the invention are to find out a method which enables producing at a high yield GADMA by reacting YDP compounds such as 2-alkoxy-3, 4-dihydro-2H-pyran or their ring-substituted derivatives and diols.
As a result of intense investigations for resolving the first problem mentioned above, it has been found out that the most sure method of producing dialdehyde monoacetals is a two-steps method; the first step of this method is the synthesis of almost pure aldehyde bisacetal via adding in a system containing dialdehyde more than twice by mole of diol with respect to one mole of dialdehyde, reacting such a system and then removing by distillation the excess amount of diol and the produced water; the second step consists of obtaining dialdehyde monoacetal via reacting the dialdehyde bisacetal obtained with dialdehyde which is a starting material and then removing by distillation produced water and the excess amount of diol.
Further, as a result of intense investigations for solving the second and third problems of the present invention, the inventors found that it is possible to nearly completely isolate GADMA without any problems regarding the reverse conversion of GADMA into GADBA which occurs during isolation of GADMA. This can be obtained via using a method consisting of a first step wherein GADMA can be obtained via reacting 2-alkoxy-3, 4-dihydro-2H-pyran and diol, and then by reacting GA with another by-product of the former reaction without hydrolysis of the first by-product due to water addition.
Further, the present inventors have discovered how to produce and isolate at a high yield GADMA via keeping the temperature of the solution in the bottom of the distillation column in a determined range during an initial distillation operation of the distillation for isolating GADMA.